Skip to content
2000
Volume 29, Issue 2
  • ISSN: 1385-2728
  • E-ISSN: 1875-5348

Abstract

A pentacyclic triterpenoid produced from medicinal herbs, fruits, and vegetables, Ursolic acid (UA) has pharmacological activity. This review provides a comprehensive overview of the interactions of UA with molecular targets, its various mechanisms of action, and its clinical implications in cancer therapy. Numerous studies have been conducted on the pharmacological effects of UA, and its biological benefits, such as its anti-inflammatory, antioxidant, and anti-cancer activities, have been demonstrated. The study showed how signaling pathways, such as PI3K/Akt, MAPK, and NF-κB, work together to control cell death, proliferation, and inflammation. UA effectively treats cancer by interacting with molecular targets in cell signaling pathways, making it a potent treatment option. It inhibits tumor cell transformation, limits their reproduction ability, and triggers apoptosis. It also has been found to inhibit various pro-inflammatory transcription factors and cell cycle proteins, such as kinases, cytokines, chemokines, adhesion molecules, and inflammatory enzymes. The targets may aid in UA's chemopreventive and therapeutic benefits by preventing cancer initiation, growth, and metastasis. UA inhibits cancer cell proliferation by arresting and triggering apoptosis through the cell cycle. It is a promising anti-cancer agent with various mechanisms of action. Additionally, it can target multiple signaling pathways and influence the tumor microenvironment, suggesting its potential as a complementary therapy in cancer treatment. Further clinical investigations are needed to entirely understand the therapeutic potential of UA and optimize its application in cancer. This review explores the molecular targets of UA and provides insights into its potential anticancer activities.

Loading

Article metrics loading...

/content/journals/coc/10.2174/0113852728320575240719052529
2024-08-06
2024-12-27
Loading full text...

Full text loading...

References

  1. DewanganJ. SrivastavaS. MishraS. DivakarA. KumarS. RathS.K. Salinomycin inhibits breast cancer progression via targeting HIF-1α/VEGF mediated tumor angiogenesis in vitro and in vivo.Biochem. Pharmacol.201916432633510.1016/j.bcp.2019.04.026 31028743
    [Google Scholar]
  2. MadeF. WilsonK. JinaR. TlotlengN. JackS. NtlebiV. KootbodienT. Distribution of cancer mortality rates by province in South Africa.Cancer Epidemiol.201751566110.1016/j.canep.2017.10.007 29040965
    [Google Scholar]
  3. RodriguesF.C. Anil KumarN.V. ThakurG. Developments in the anticancer activity of structurally modified curcumin: An up-to-date review.Eur. J. Med. Chem.20191777610410.1016/j.ejmech.2019.04.058 31129455
    [Google Scholar]
  4. KhwazaV. OyedejiO.O. AderibigbeB.A. Ursolic acid-based derivatives as potential anti-cancer agents: An update.Int. J. Mol. Sci.20202116592010.3390/ijms21165920 32824664
    [Google Scholar]
  5. YinR. LiT. TianJ.X. XiP. LiuR.H. Ursolic acid, a potential anticancer compound for breast cancer therapy.Crit. Rev. Food Sci. Nutr.201858456857410.1080/10408398.2016.1203755 27469428
    [Google Scholar]
  6. KassiE. SourlingasT.G. SpiliotakiM. PapoutsiZ. PratsinisH. AligiannisN. MoutsatsouP. Ursolic acid triggers apoptosis and Bcl-2 downregulation in MCF-7 breast cancer cells.Cancer Invest.200927772373310.1080/07357900802672712 19440893
    [Google Scholar]
  7. XavierC.P.R. LimaC.F. PretoA. SerucaR. Fernandes-FerreiraM. Pereira-WilsonC. Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells.Cancer Lett.2009281216217010.1016/j.canlet.2009.02.041 19344998
    [Google Scholar]
  8. YimE.K. LeeK.H. NamkoongS.E. UmS.J. ParkJ.S. Proteomic analysis of ursolic acid-induced apoptosis in cervical carcinoma cells.Cancer Lett.2006235220922010.1016/j.canlet.2005.04.007 15925442
    [Google Scholar]
  9. KanzawaT. KondoY. ItoH. KondoS. GermanoI. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide.Cancer Res.200363921032108 12727826
    [Google Scholar]
  10. OpipariA.W.Jr TanL. BoitanoA.E. SorensonD.R. AuroraA. LiuJ.R. Resveratrol-induced autophagocytosis in ovarian cancer cells.Cancer Res.200464269670310.1158/0008‑5472.CAN‑03‑2404 14744787
    [Google Scholar]
  11. EllingtonA.A. BerhowM. SingletaryK.W. Induction of macroautophagy in human colon cancer cells by soybean B-group triterpenoid saponins.Carcinogenesis200426115916710.1093/carcin/bgh297 15471899
    [Google Scholar]
  12. LewinskaA. Adamczyk-GrochalaJ. KwasniewiczE. DeregowskaA. WnukM. Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells.Apoptosis201722680081510.1007/s10495‑017‑1353‑7 28213701
    [Google Scholar]
  13. ElstromR.L. BauerD.E. BuzzaiM. KarnauskasR. HarrisM.H. PlasD.R. ZhuangH. CinalliR.M. AlaviA. RudinC.M. ThompsonC.B. Akt stimulates aerobic glycolysis in cancer cells.Cancer Res.200464113892389910.1158/0008‑5472.CAN‑03‑2904 15172999
    [Google Scholar]
  14. RobeyR.B. HayN. Eds.; Is Akt the “Warburg kinase”?—Akt-energy metabolism interactions and oncogenesis. Seminars in cancer biology.AmsterdamElsevier2009
    [Google Scholar]
  15. ZhengQ. JinF. YaoC. ZhangT. ZhangG. AiX. Ursolic acid-induced AMP-activated protein kinase (AMPK) activation contributes to growth inhibition and apoptosis in human bladder cancer T24 cells.Biochem. Biophys. Res. Commun.2012419474174710.1016/j.bbrc.2012.02.093 22387548
    [Google Scholar]
  16. LiJ. LiangX. YangX. Ursolic acid inhibits growth and induces apoptosis in gemcitabine-resistant human pancreatic cancer via the JNK and PI3K/Akt/NF-κB pathways.Oncol. Rep.201228250151010.3892/or.2012.1827 22641480
    [Google Scholar]
  17. LinC.W. ChinH.K. LeeS.L. ChiuC.F. ChungJ.G. LinZ.Y. WuC.Y. LiuY.C. HsiaoY.T. FengC.H. BaiL.Y. WengJ.R. Ursolic acid induces apoptosis and autophagy in oral cancer cells.Environ. Toxicol.201934998399110.1002/tox.22769 31062913
    [Google Scholar]
  18. YanS. HuangC. WuS. YinM. Oleanolic acid and ursolic acid induce apoptosis in four human liver cancer cell lines.Toxicol. In vitro 201024384284810.1016/j.tiv.2009.12.008 20005942
    [Google Scholar]
  19. SeoD.Y. LeeS.R. HeoJ.W. NoM.H. RheeB.D. KoK.S. KwakH.B. HanJ. Ursolic acid in health and disease.Korean J. Physiol. Pharmacol.201822323524810.4196/kjpp.2018.22.3.235 29719446
    [Google Scholar]
  20. GeY. Ursolic acid induce anoikis by suppress metabolism in ovarian cancer cells.Ann. Oncol.201930vi14510.1093/annonc/mdz343.127
    [Google Scholar]
  21. KassiE. PapoutsiZ. PratsinisH. AligiannisN. ManoussakisM. MoutsatsouP. Ursolic acid, a naturally occurring triterpenoid, demonstrates anticancer activity on human prostate cancer cells.J. Cancer Res. Clin. Oncol.2007133749350010.1007/s00432‑007‑0193‑1 17516089
    [Google Scholar]
  22. SubramanianC. SolairajaS. DunnaN.R. VenkatabalasubramanianS. Toxicity, safety, and pharmacotherapeutic properties of ursolic acid: Current status, challenges, and future perspectives against lung cancer.Curr. Bioact. Compd.2023195e24102221033310.2174/1573407219666221024142326
    [Google Scholar]
  23. SarwarM.S. RamirezC.N. KuoH.C.D. ChouP. WuR. SargsyanD. YangY. ShannarA. PeterR.M. YinR. WangY. SuX. KongA.N. Triterpenoid ursolic acid regulates the environmental carcinogen benzo[a]pyrene-driven epigenetic and metabolic alterations in SKH-1 hairless mice for skin cancer interception.Carcinogenesis202445528829910.1093/carcin/bgae009 38466106
    [Google Scholar]
  24. YangG. YangT. ZhangW. LuM. MaX. XiangG. In vitro and in vivo antitumor effects of folate-targeted ursolic acid stealth liposome.J. Agric. Food Chem.201462102207221510.1021/jf405675g 24528163
    [Google Scholar]
  25. López-HortasL. Pérez-LarránP. González-MuñozM.J. FalquéE. DomínguezH. Recent developments on the extraction and application of ursolic acid. A review.Food Res. Int.201810313014910.1016/j.foodres.2017.10.028 29389599
    [Google Scholar]
  26. RoutK.K. SinghR.K. BarikD.P. MishraS.K. Thin-Layer chromatographic separation and validated HPTLC method for quantification of Ursolic acid in various Ocimum species.Yao Wu Shi Pin Fen Xi201220422
    [Google Scholar]
  27. YamaguchiH. NoshitaT. KidachiY. UmetsuH. HayashiM. KomiyamaK. FunayamaS. RyoyamaK. Isolation of ursolic acid from apple peels and its specific efficacy as a potent antitumor agent.J. Health Sci.200854665466010.1248/jhs.54.654
    [Google Scholar]
  28. Stiti, N; Hartmann, M-A Nonsterol triterpenoids as major constituents of Olea europaea.J. Lipids20122012476595
    [Google Scholar]
  29. IkedaY. MurakamiA. OhigashiH. Ursolic acid: An anti‐ and pro‐inflammatory triterpenoid.Mol. Nutr. Food Res.2008521264210.1002/mnfr.200700389 18203131
    [Google Scholar]
  30. LealA.S. WangR. SalvadorJ.A.R. JingY. Synthesis of novel ursolic acid heterocyclic derivatives with improved abilities of antiproliferation and induction of p53, p21waf1 and NOXA in pancreatic cancer cells.Bioorg. Med. Chem.201220195774578610.1016/j.bmc.2012.08.010 22959527
    [Google Scholar]
  31. VazquezA.M. AimarM.L. DemmelG.I. CriadoS.G. Determination of volatile organic compounds of Tagetes argentina Cabrera (Asteraceae) using HS-SPME analysis.Bol. Latinoam. Caribe Plantas Med. Aromat.2011105463469
    [Google Scholar]
  32. SonJ. LeeS.Y. Therapeutic potential of ursonic acid: Comparison with ursolic acid.Biomolecules20201011150510.3390/biom10111505 33147723
    [Google Scholar]
  33. SunQ. HeM. ZhangM. ZengS. ChenL. ZhouL. XuH. Ursolic acid: A systematic review of its pharmacology, toxicity and rethink on its pharmacokinetics based on PK-PD model.Fitoterapia202014710473510.1016/j.fitote.2020.104735 33010369
    [Google Scholar]
  34. WanS.Z. LiuC. HuangC.K. LuoF.Y. ZhuX. Ursolic acid improves intestinal damage and bacterial dysbiosis in liver fibrosis mice.Front. Pharmacol.201910132110.3389/fphar.2019.01321 31736766
    [Google Scholar]
  35. YuD. KanZ. ShanF. ZangJ. ZhouJ. Triple strategies to improve oral bioavailability by fabricating coamorphous forms of ursolic acid with piperine: Enhancing water-solubility, permeability, and inhibiting cytochrome p450 isozymes.Mol. Pharm.202017124443446210.1021/acs.molpharmaceut.0c00443 32926628
    [Google Scholar]
  36. KalaniK. YadavD.K. KhanF. SrivastavaS.K. SuriN. Pharmacophore, QSAR, and ADME based semisynthesis and in vitro evaluation of ursolic acid analogs for anticancer activity.J. Mol. Model.20121873389341310.1007/s00894‑011‑1327‑6 22271093
    [Google Scholar]
  37. KalaniK. YadavD. SinghA. KhanF. GodboleM.M. SrivastavaS.K. QSAR guided semi-synthesis and in-vitro validation of anticancer activity in ursolic acid derivatives.Curr. Top. Med. Chem.20141481005101310.2174/1568026614666140324121606 24660684
    [Google Scholar]
  38. SalvadorJ.A.R. LealA.S. AlhoD.P.S. GonçalvesB.M.F. ValdeiraA.S. MendesV.I.S. JingY. Highlights of pentacyclic triterpenoids in the cancer settings.Stud. Nat. Prod. Chem.201441337310.1016/B978‑0‑444‑63294‑4.00002‑4
    [Google Scholar]
  39. AliS. AlamM. KhatoonF. FatimaU. ElasbaliA.M. AdnanM. IslamA. HassanM.I. SnoussiM. De FeoV. Natural products can be used in therapeutic management of COVID-19: Probable mechanistic insights.Biomed. Pharmacother.202214711265810.1016/j.biopha.2022.112658 35066300
    [Google Scholar]
  40. YuF. ThammA.M.K. ReedD. Villa-RuanoN. QuesadaA.L. GloriaE.L. CovelloP. De LucaV. Functional characterization of amyrin synthase involved in ursolic acid biosynthesis in Catharanthus roseus leaf epidermis.Phytochemistry20139112212710.1016/j.phytochem.2012.05.002 22652241
    [Google Scholar]
  41. PaluD. BighelliA. CasanovaJ. PaoliM. Identification and quantitation of ursolic and oleanolic acids in Ilex aquifolium L. Leaf extracts using 13C and 1H-NMR spectroscopy.Molecules20192423441310.3390/molecules24234413 31816870
    [Google Scholar]
  42. MazumderK. SiwuE.R.O. NozakiS. WatanabeY. TanakaK. FukaseK. Ursolic acid derivatives from Bangladeshi medicinal plant, Saurauja roxburghii: Isolation and cytotoxic activity against A431 and C6 glioma cell lines.Phytochem. Lett.20114328729110.1016/j.phytol.2011.04.019
    [Google Scholar]
  43. AliS.A. IbrahimN.A. MohammedM.M.D. El-HawaryS. RefaatE.A. The potential chemo preventive effect of ursolic acid isolated from Paulownia tomentosa, against N-diethylnitrosamine: Initiated and promoted hepatocarcinogenesis.Heliyon201955e0176910.1016/j.heliyon.2019.e01769 31193530
    [Google Scholar]
  44. JungT.Y. PhamT.N.N. UmeyamaA. ShojiN. HashimotoT. LeeJ.J. TakeiM. Ursolic acid isolated from Uncaria rhynchophylla activates human dendritic cells via TLR2 and/or TLR4 and induces the production of IFN-γ by CD4+ naïve T cells.Eur. J. Pharmacol.20106432-329730310.1016/j.ejphar.2010.06.030 20599915
    [Google Scholar]
  45. AmarowiczR. PeggR.B. Inhibition of proliferation of human carcinoma cell lines by phenolic compounds from a bearberry-leaf crude extract and its fractions.J. Funct. Foods20135266066710.1016/j.jff.2013.01.009
    [Google Scholar]
  46. KwonS.H. ParkH.Y. KimJ.Y. JeongI.Y. LeeM.K. SeoK.I. Apoptotic action of ursolic acid isolated from Corni fructus in RC-58T/h/SA#4 primary human prostate cancer cells.Bioorg. Med. Chem. Lett.201020226435643810.1016/j.bmcl.2010.09.073 20943386
    [Google Scholar]
  47. KubatkaP. UramovaS. KelloM. KajoK. SamecM. JasekK. VybohovaD. LiskovaA. MojzisJ. AdamkovM. ZuborP. SmejkalK. SvajdlenkaE. SolarP. SamuelS.M. ZulliA. KassayovaM. LasabovaZ. KwonT.K. PecM. DankoJ. BüsselbergD. Anticancer activities of Thymus vulgaris L. in experimental breast carcinoma in vivo and in vitro.Int. J. Mol. Sci.2019207174910.3390/ijms20071749 30970626
    [Google Scholar]
  48. RicheriouxN. BlondeauC. WiedemannA. RémyS. VautherotJ-F. DenesvreC. Rho-ROCK and Rac-PAK signaling pathways have opposing effects on the cell-to-cell spread of Marek’s disease virus.PLoS One201278e4407210.1371/journal.pone.0044072
    [Google Scholar]
  49. MuD. ZhouG. LiJ. SuB. GuoH. Ursolic acid activates the apoptosis of prostate cancer via ROCK/PTEN mediated mitochondrial translocation of cofilin-1.Oncol. Lett.201815332023206 29435058
    [Google Scholar]
  50. WuB. WangX. ChiZ. HuR. ZhangR. YangW. LiuZ. Ursolic acid-induced apoptosis in K562 cells involving upregulation of PTEN gene expression and inactivation of the PI3K/Akt pathway.Arch. Pharm. Res.201235354354810.1007/s12272‑012‑0318‑1 22477202
    [Google Scholar]
  51. ParkJ.H. KwonH.Y. SohnE.J. KimK.A. KimB. JeongS.J. SongJ. KooJ.S. KimS.H. Inhibition of Wnt/β-catenin signaling mediates ursolic acid-induced apoptosis in PC-3 prostate cancer cells.Pharmacol. Rep.20136551366137410.1016/S1734‑1140(13)71495‑6 24399733
    [Google Scholar]
  52. LiS. WuR. WangL. DinaKuo H.C.; Sargsyan, D.; Zheng, X.; Wang, Y.; Su, X.; Kong, A.N. Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer.Mol. Carcinog.202261111112110.1002/mc.23365 34727410
    [Google Scholar]
  53. PetermannA. MieneC. Schulz-RaffeltG. PaligeK. HölzerJ. GleiM. BöhmerF.D. GSTT2, a phase II gene induced by apple polyphenols, protects colon epithelial cells against genotoxic damage.Mol. Nutr. Food Res.200953101245125310.1002/mnfr.200900110 19753610
    [Google Scholar]
  54. WangC. ShuL. ZhangC. LiW. WuR. GuoY. YangY. KongA.N. Histone methyltransferase Setd7 regulates Nrf2 signaling pathway by phenethyl isothiocyanate and ursolic acid in human prostate cancer cells.Mol. Nutr. Food Res.20186218170084010.1002/mnfr.201700840 29383876
    [Google Scholar]
  55. ShanmugamM.K. RajendranP. LiF. NemaT. ValiS. AbbasiT. KapoorS. SharmaA. KumarA.P. HoP.C. HuiK.M. SethiG. Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice.J. Mol. Med. (Berl.)201189771372710.1007/s00109‑011‑0746‑2 21465181
    [Google Scholar]
  56. FardM.H. BeydokhtiH. TahergorabiZ. AbediniM.R. MitraM. “Ziziphus jujuba”: A red fruit with promising anticancer activities.Pharmacogn. Rev.20159189910610.4103/0973‑7847.162108 26392706
    [Google Scholar]
  57. ChanE.W.C. SoonC.Y. TanJ.B.L. WongS.K. HuiY.W. Ursolic acid: An overview on its cytotoxic activities against breast and colorectal cancer cells.J. Integr. Med.201917315516010.1016/j.joim.2019.03.003 30928277
    [Google Scholar]
  58. ZhaoC. YinS. DongY. GuoX. FanL. YeM. HuH. Autophagy-dependent EIF2AK3 activation compromises ursolic acid-induced apoptosis through upregulation of MCL1 in MCF-7 human breast cancer cells.Autophagy20139219620710.4161/auto.22805 23182854
    [Google Scholar]
  59. CargninS.T. GnoattoS.B. Ursolic acid from apple pomace and traditional plants: A valuable triterpenoid with functional properties.Food Chem.201722047748910.1016/j.foodchem.2016.10.029 27855928
    [Google Scholar]
  60. LiW. ZhangH. NieM. WangW. LiuZ. ChenC. ChenH. LiuR. BalochZ. MaK. A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines.Oncol. Lett.201815223232329 29434940
    [Google Scholar]
  61. YehC.T. WuC.H. YenG.C. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c‐Jun N ‐terminal kinase, Akt and mammalian target of rapamycin signaling.Mol. Nutr. Food Res.20105491285129510.1002/mnfr.200900414 20352621
    [Google Scholar]
  62. JinH. PiJ. YangF. JiangJ. WangX. BaiH. ShaoM. HuangL. ZhuH. YangP. LiL. LiT. CaiJ. ChenZ.W. Folate-chitosan nanoparticles loaded with ursolic acid confer anti-breast cancer activities in vitro and in vivo.Sci. Rep.2016613078210.1038/srep30782 27469490
    [Google Scholar]
  63. RashidS. DarB.A. MajeedR. HamidA. BhatB.A. Synthesis and biological evaluation of ursolic acid-triazolyl derivatives as potential anti-cancer agents.Eur. J. Med. Chem.20136623824510.1016/j.ejmech.2013.05.029 23811086
    [Google Scholar]
  64. LinL. LiuA. PengZ. LinH.J. LiP.K. LiC. LinJ. STAT3 is necessary for proliferation and survival in colon cancer-initiating cells.Cancer Res.201171237226723710.1158/0008‑5472.CAN‑10‑4660 21900397
    [Google Scholar]
  65. WangW. ZhaoC. JouD. LüJ. ZhangC. LinL. LinJ. Ursolic acid inhibits the growth of colon cancer-initiating cells by targeting STAT3.Anticancer Res.2013331042794284 24122993
    [Google Scholar]
  66. AlamM. AliS. AhmedS. ElasbaliA.M. AdnanM. IslamA. HassanM.I. YadavD.K. Therapeutic potential of ursolic acid in cancer and diabetic neuropathy diseases.Int. J. Mol. Sci.202122221216210.3390/ijms222212162 34830043
    [Google Scholar]
  67. HutchesonI.R. KnowldenJ.M. MaddenT.A. BarrowD. GeeJ.M.W. WakelingA.E. NicholsonR.I. Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells.Breast Cancer Res. Treat.2003811819310.1023/A:1025484908380 14531500
    [Google Scholar]
  68. YuS-G. ZhangC-J. XuX-E. SunJ-H. ZhangL. YuP-F. Ursolic acid derivative ameliorates streptozotocin-induced diabestic bone deleterious effects in mice.Int. J. Clin. Exp. Pathol.20158436813690 26097549
    [Google Scholar]
  69. KashyapD. SharmaA. TuliH.S. PuniaS. SharmaA.K. Ursolic acid and oleanolic acid: Pentacyclic terpenoids with promising anti-inflammatory activities.Recent Pat. Inflamm. Allergy Drug Discov.2016101213310.2174/1872213X10666160711143904 27531153
    [Google Scholar]
  70. KimK. ShinE.A. JungJ.H. ParkJ.E. KimD.S. ShimB.S. KimS.H. Ursolic acid induces apoptosis in colorectal cancer cells partially via upregulation of MicroRNA-4500 and inhibition of JAK2/STAT3 phosphorylation.Int. J. Mol. Sci.201820111410.3390/ijms20010114 30597956
    [Google Scholar]
  71. YuF.Y. TuY. DengY. GuoC. NingJ. ZhuY. LvX. YeH. MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2.Cancer Biol. Ther.201617111149115710.1080/15384047.2016.1235661 27686621
    [Google Scholar]
  72. LinJ. ChenY. WeiL. HongZ. SferraT.J. PengJ. Ursolic acid inhibits colorectal cancer angiogenesis through suppression of multiple signaling pathways.Int. J. Oncol.20134351666167410.3892/ijo.2013.2101 24042330
    [Google Scholar]
  73. PrasadS. YadavV.R. SungB. GuptaS.C. TyagiA.K. AggarwalB.B. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment.Oncotarget2016711131821319610.18632/oncotarget.7537 26909608
    [Google Scholar]
  74. LinJ.H. ChenS.Y. LuC.C. LinJ.A. YenG.C. Ursolic acid promotes apoptosis, autophagy, and chemosensitivity in gemcitabine‐resistant human pancreatic cancer cells.Phytother. Res.20203482053206610.1002/ptr.6669 32185829
    [Google Scholar]
  75. LiaZ-Y. ChenaS-Y. YenG-C. YenG-C. Ursolic acid restores sensitivity to gemcitabine through the RAGE/NF-κB/MDR1 axis in pancreatic cancer cells and in a mouse xenograft model.Yao Wu Shi Pin Fen Xi202129226227410.38212/2224‑6614.3346 35696208
    [Google Scholar]
  76. MullenP.J. YuR. LongoJ. ArcherM.C. PennL.Z. The interplay between cell signalling and the mevalonate pathway in cancer.Nat. Rev. Cancer2016161171873110.1038/nrc.2016.76 27562463
    [Google Scholar]
  77. KimG.H. KanS.Y. KangH. LeeS. KoH.M. KimJ.H. LimJ.H. Ursolic acid suppresses cholesterol biosynthesis and exerts anti-cancer effects in hepatocellular carcinoma cells.Int. J. Mol. Sci.20192019476710.3390/ijms20194767 31561416
    [Google Scholar]
  78. ShahabU. AhmadM.K. MahdiA.A. WaseemM. ArifB. AhmadS. Eds.; The receptor for advanced glycation end products: A fuel to pancreatic cancer. Seminars in Cancer Biology.AmsterdamElsevier20183743
    [Google Scholar]
  79. KangR. TangD. LiveseyK.M. SchapiroN.E. LotzeM.T. ZehH.J.III The Receptor for Advanced Glycation End-products (RAGE) protects pancreatic tumor cells against oxidative injury.Antioxid. Redox Signal.20111582175218410.1089/ars.2010.3378 21126167
    [Google Scholar]
  80. KangR HouW ZhangQ ChenR LeeY BartlettD RAGE is essential for oncogenic KRAS-mediated hypoxic signaling in pancreatic cancer.Cell Death Dis.2014510e1480-e
    [Google Scholar]
  81. NiikawaM. HayashiH. SatoT. NagaseH. KitoH. Isolation of substances from glossy privet (Ligustrum lucidum Ait.) inhibiting the mutagenicity of benzo [a] pyrene in bacteria. Mutation Res/Genet.Toxicol.1993319119
    [Google Scholar]
  82. PolyaG.M. PolyaG.M. Selective inhibition of cyclic AMP-dependent protein kinase by amphiphilic triterpenoids and related compounds.Phytochemistry1996411556310.1016/0031‑9422(95)00583‑8 8588874
    [Google Scholar]
  83. GuevaraA.P. AmorE. RussellG. Antimutagens from Plumeria acuminata ait. Mutation Res.Environ. Mutag. Related Sub.19963612-316717210.1016/S0165‑1161(96)90240‑X
    [Google Scholar]
  84. YoungH. ChungH. LeeC. ParkK. YokozawaT. OuraH. Ursolic acid inhibits aflatoxin B1-induced mutagenicity in a Salmonella assay system.Biol. Pharm. Bull.199417799099210.1248/bpb.17.990 8000393
    [Google Scholar]
  85. HuangM-T. HoC-T. WangZ.Y. FerraroT. LouY-R. StauberK. MaW. GeorgiadisC. LaskinJ.D. ConneyA.H. Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid.Cancer Res.1994543701708 8306331
    [Google Scholar]
  86. OhigashiH. TakamuraH. KoshimizuK. TokudaH. ItoY. Search for possible antitumor promoters by inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epstein-barr virus activation; ursolic acid and oleanolic acid from an anti-inflammatory chinese medicinal plant, Glechoma hederaceae L.Cancer Lett.198630214315110.1016/0304‑3835(86)90082‑0 3006912
    [Google Scholar]
  87. HsuY.L. KuoP.L. LinC.C. Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells.Life Sci.200475192303231610.1016/j.lfs.2004.04.027 15350828
    [Google Scholar]
  88. BaekJ.H. LeeY.S. KangC.M. KimJ.A. KwonK.S. SonH.C. KimK.W. Intracellular Ca2+ release mediates ursolic acid–induced apoptosis in human leukemic HL-60 cells.Int. J. Cancer199773572572810.1002/(SICI)1097‑0215(19971127)73:5<725::AID‑IJC19>3.0.CO;2‑4 9398053
    [Google Scholar]
  89. MáñezS. RecioM.C. GinerR.M. RíosJ.L. Effect of selected triterpenoids on chronic dermal inflammation.Eur. J. Pharmacol.1997334110310510.1016/S0014‑2999(97)01187‑4 9346335
    [Google Scholar]
  90. WangX. IkejimaK. KonK. AraiK. AoyamaT. OkumuraK. AbeW. SatoN. WatanabeS. Ursolic acid ameliorates hepatic fibrosis in the rat by specific induction of apoptosis in hepatic stellate cells.J. Hepatol.201155237938710.1016/j.jhep.2010.10.040 21168456
    [Google Scholar]
  91. DengL. ZhangR. TangF. LiC. XingY.Y. XiT. Ursolic acid induces U937 cells differentiation by PI3K/Akt pathway activation.Chin. J. Nat. Med.2014121151910.1016/S1875‑5364(14)60003‑0 24484591
    [Google Scholar]
  92. LeeH.Y. ChungH.Y. KimK.H. LeeJ.J. KimK.W. Induction of differentiation in the cultured F9 teratocarcinoma stem cells by triterpene acids.J. Cancer Res. Clin. Oncol.1994120951351810.1007/BF01221027 8045916
    [Google Scholar]
  93. PaikK.J. JeonS.S. ChungH.Y. LeeK.H. KimK.W. ChungJ.K. KimN.D. Induction of differentiation of the cultured rat mammary epithelial cells by triterpene acids.Arch. Pharm. Res.199821439840510.1007/BF02974633 9875466
    [Google Scholar]
  94. ChaH-J. BaeS-K. LeeH-Y. LeeO-H. SatoH. SeikiM. ParkB.C. KimK.W. Anti-invasive activity of ursolic acid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT1080 human fibrosarcoma cells.Cancer Res.1996561022812284 8625299
    [Google Scholar]
  95. ChaH.J. ParkM.T. ChungH.Y. KimN.D. SatoH. SeikiM. KimK.W. Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells.Oncogene199816677177810.1038/sj.onc.1201587 9488041
    [Google Scholar]
  96. SilvaA.M. AlvaradoH.L. AbregoG. Martins-GomesC. Garduño-RamirezM.L. GarcíaM.L. CalpenaA.C. SoutoE.B. In vitro cytotoxicity of oleanolic/ursolic acids-loaded in PLGA nanoparticles in different cell lines.Pharmaceutics201911836210.3390/pharmaceutics11080362 31344882
    [Google Scholar]
  97. HsuH.Y. YangJ.J. LinC.C. Effects of oleanolic acid and ursolic acid on inhibiting tumor growth and enhancing the recovery of hematopoietic system postirradiation in mice.Cancer Lett.19971111-271310.1016/S0304‑3835(96)04481‑3 9022122
    [Google Scholar]
  98. Es-saadyD. SimonA. OllierM. MaurizisJ.C. ChuliaA.J. DelageC. Inhibitory effect of ursolic acid on B16 proliferation through cell cycle arrest.Cancer Lett.1996106219319710.1016/0304‑3835(96)04312‑1 8844972
    [Google Scholar]
  99. MizushinaY. IidaA. OhtaK. SugawaraF. SakaguchiK. Novel triterpenoids inhibit both DNA polymerase and DNA topoisomerase.Biochem. J.2000350375776310.1042/bj3500757 10970789
    [Google Scholar]
  100. Es-SaadyD. SimonA. Jayat-VignolesC. ChuliaA.J. DelageC. MCF-7 cell cycle arrested at G1 through ursolic acid, and increased reduction of tetrazolium salts.Anticancer Res.1996161481486 8615658
    [Google Scholar]
  101. MazumderK. TanakaK. FukaseK. Cytotoxic activity of ursolic acid derivatives obtained by isolation and oxidative derivatization.Molecules20131888929894410.3390/molecules18088929 23896618
    [Google Scholar]
  102. LiaoQ. YangW. JiaY. ChenX. GaoQ. BiK. LC-MS determination and pharmacokinetic studies of ursolic acid in rat plasma after administration of the traditional Chinese medicinal preparation Lu-Ying extract.Yakugaku Zasshi2005125650951510.1248/yakushi.125.509 15930819
    [Google Scholar]
  103. BabalolaI.T. ShodeF.O. Ubiquitous ursolic acid: A potential pentacyclic triterpene natural product.J. Pharmacogn. Phytochem.201322214222
    [Google Scholar]
  104. MlalaS. OyedejiA.O. GondweM. OyedejiO.O. Ursolic acid and its derivatives as bioactive agents.Molecules20192415275110.3390/molecules24152751 31362424
    [Google Scholar]
  105. ChenH. GaoY. WangA. ZhouX. ZhengY. ZhouJ. Evolution in medicinal chemistry of ursolic acid derivatives as anticancer agents.Eur. J. Med. Chem.20159264865510.1016/j.ejmech.2015.01.031 25617694
    [Google Scholar]
  106. HuaS.X. HuangR.Z. YeM.Y. PanY.M. YaoG.Y. ZhangY. WangH.S. Design, synthesis and in vitro evaluation of novel ursolic acid derivatives as potential anticancer agents.Eur. J. Med. Chem.20159543545210.1016/j.ejmech.2015.03.051 25841199
    [Google Scholar]
  107. XuJ. WangX. ZhangH. YueJ. SunY. ZhangX. ZhaoY. Synthesis of triterpenoid derivatives and their anti-tumor and anti-hepatic fibrosis activities.Nat. Prod. Res.202034676677210.1080/14786419.2018.1499642 30445851
    [Google Scholar]
  108. ShaoJ.W. DaiY.C. XueJ.P. WangJ.C. LinF.P. GuoY.H. In vitro and in vivo anticancer activity evaluation of ursolic acid derivatives.Eur. J. Med. Chem.20114672652266110.1016/j.ejmech.2011.03.050 21514015
    [Google Scholar]
  109. SingletaryK. MacDonaldC. WalligM. Inhibition by rosemary and carnosol of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation.Cancer Lett.19961041434810.1016/0304‑3835(96)04227‑9 8640744
    [Google Scholar]
  110. Alzate FilhoM. FranchinT. JonataM. OliveiraA. CandidoC. FuriniJ. Kinetic disposition of ursolic acid in rats.Pharm. Biomed. Res.201842531
    [Google Scholar]
  111. ZhaoW.J. WangB.J. WeiC.M. YuanG.Y. BuF.L. GuoR.C. Determination of glycyrrhetic acid in human plasma by HPLC-MS method and investigation of its pharmacokinetics.J. Clin. Pharm. Ther.200833328929410.1111/j.1365‑2710.2008.00899.x 18452416
    [Google Scholar]
  112. ZhengX.C. WangS.H. Determination of asiatic acid in beagle dog plasma after oral administration of Centella asiatica extract by precolumn derivatization RP-HPLC.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.20098775-647748110.1016/j.jchromb.2008.11.045 19167274
    [Google Scholar]
  113. WangM. ZhaoT. LiuY. WangQ. XingS. LiL. WangL. LiuL. GaoD. Ursolic acid liposomes with chitosan modification: Promising antitumor drug delivery and efficacy.Mater. Sci. Eng. C2017711231124010.1016/j.msec.2016.11.014 27987679
    [Google Scholar]
  114. YoonY. LimJ.W. KimJ. KimY. ChunK.H. Discovery of ursolic acid prodrug (NX-201): Pharmacokinetics and in vivo antitumor effects in PANC-1 pancreatic cancer.Bioorg. Med. Chem. Lett.201626225524552710.1016/j.bmcl.2016.10.008 27769622
    [Google Scholar]
  115. ZhuZ. QianZ. YanZ. ZhaoC. WangH. YingG. A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors.Int. J. Nanomedicine20138129136 23319864
    [Google Scholar]
  116. QianZ. WangX. SongZ. ZhangH. ZhouS. ZhaoJ. A phase I trial to evaluate the multiple-dose safety and antitumor activity of ursolic acid liposomes in subjects with advanced solid tumors.BioMed Res. Int.2015201580971410.1155/2015/809714
    [Google Scholar]
  117. WangX.H. ZhouS.Y. QianZ.Z. ZhangH.L. QiuL.H. SongZ. ZhaoJ. WangP. HaoX.S. WangH.Q. Evaluation of toxicity and single-dose pharmacokinetics of intravenous ursolic acid liposomes in healthy adult volunteers and patients with advanced solid tumors.Expert Opin. Drug Metab. Toxicol.20139211712510.1517/17425255.2013.738667 23134084
    [Google Scholar]
  118. BothD.M. GoodtzovaK. YaroshD.B. BrownD.A. Liposome-encapsulated ursolic acid increases ceramides and collagen in human skin cells.Arch. Dermatol. Res.20022931156957510.1007/s00403‑001‑0272‑0 11876525
    [Google Scholar]
  119. TokudaH. OhigashiH. KoshimizuK. ItoY. Inhibitory effects of ursolic and oleanolic ancid on skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.Cancer Lett.198633327928510.1016/0304‑3835(86)90067‑4 3802058
    [Google Scholar]
  120. SomovaL.I. ShodeF.O. RamnananP. NadarA. Antihypertensive, antiatherosclerotic and antioxidant activity of triterpenoids isolated from Olea europaea, subspecies africana leaves.J. Ethnopharmacol.2003842-329930510.1016/S0378‑8741(02)00332‑X 12648829
    [Google Scholar]
  121. SomovaL.I. ShodeF.O. MipandoM. Cardiotonic and antidysrhythmic effects of oleanolic and ursolic acids, methyl maslinate and uvaol.Phytomedicine2004112-312112910.1078/0944‑7113‑00329 15070161
    [Google Scholar]
  122. Prakash ChaturvedulaV.S. GaoZ. HechtS.M. JonesS.H. KingstonD.G.I. A new acylated oleanane triterpenoid from Couepia polyandra that inhibits the lyase activity of DNA polymerase β.J. Nat. Prod.200366111463146510.1021/np0301893 14640519
    [Google Scholar]
  123. Giner-LarzaE.M. MáñezS. RecioM.C. GinerR.M. PrietoJ.M. Cerdá-NicolásM. RíosJ.L. Oleanonic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity.Eur. J. Pharmacol.2001428113714310.1016/S0014‑2999(01)01290‑0 11779030
    [Google Scholar]
  124. DatN.T. LeeI.S. CaiX.F. ShenG. KimY.H. Oleanane triterpenoids with inhibitory activity against NFAT transcription factor from Liquidambar formosana.Biol. Pharm. Bull.200427342642810.1248/bpb.27.426 14993816
    [Google Scholar]
  125. JovelE.M. ZhouX.L. MingD.S. WahbeT.R. TowersG.H.N. Bioactivity-guided isolation of the active compounds from Rosa nutkana and quantitative analysis of ascorbic acid by HPLCThis article is one of a selection of papers published in this special issue (part 1 of 2) on the Safety and Efficacy of Natural Health Products.Can. J. Physiol. Pharmacol.200785986587110.1139/Y07‑053 18066132
    [Google Scholar]
  126. Tin-WaM. FarnsworthN.R. FongH.H. TrojanekJ. Catharanthus alkaloids. XXV. Isolation of leurosine and ursolic acid from C. pusillus.Lloydia1970332261263 5495515
    [Google Scholar]
  127. LeeI. LeeJ. LeeY.H. LeonardJ. Ursolic acid-induced changes in tumor growth, O2 consumption, and tumor interstitial fluid pressure.Anticancer Res.2001214A28272833 11724362
    [Google Scholar]
  128. LuoJ. HuY.L. WangH. Ursolic acid inhibits breast cancer growth by inhibiting proliferation, inducing autophagy and apoptosis, and suppressing inflammatory responses via the PI3K/AKT and NF-κB signaling pathways in vitro.Exp. Ther. Med.20171443623363110.3892/etm.2017.4965 29042957
    [Google Scholar]
  129. LiuL. ZhangJ. LiM. ZhangX. ZhangJ. LiZ. WangL. WuJ. LuoC. Inhibition of HepG2 cell proliferation by ursolic acid and polysaccharides via the downregulation of cyclooxygenase-2.Mol. Med. Rep.2014962505251110.3892/mmr.2014.2059 24638056
    [Google Scholar]
  130. GuoJ.L. HanT. BaoL. LiX.M. MaJ.Q. TangL.P. Ursolic acid promotes the apoptosis of cervical cancer cells by regulating endoplasmic reticulum stress.J. Obstet. Gynaecol. Res.201945487788110.1111/jog.13919 30632222
    [Google Scholar]
  131. LiuK. GuoL. MiaoL. BaoW. YangJ. LiX. XiT. ZhaoW. Ursolic acid inhibits epithelial–mesenchymal transition by suppressing the expression of astrocyte-elevated gene-1 in human nonsmall cell lung cancer A549 cells.Anticancer Drugs201324549450310.1097/CAD.0b013e328360093b 23511428
    [Google Scholar]
  132. GaiW.T. YuD.P. WangX.S. WangP.T. Anti-cancer effect of ursolic acid activates apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin-1 in prostate cancer.Oncol. Lett.20161242880288510.3892/ol.2016.5015 27698874
    [Google Scholar]
  133. ZhengQ.F. SunH.X. HeQ.J. YeY.P. Induction of apoptosis in HeLa cells by 3β-hydroxyurs-12-en-27-oic acid.Chem. Biodivers.20063774275310.1002/cbdv.200690076 17193306
    [Google Scholar]
  134. QiuL. ZhaoX. ZuY. ZhangY. LiuY. WuW. LiY. Ursolic acid nanoparticles for oral delivery prepared by emulsion solvent evaporation method: Characterization, in vitro evaluation of radical scavenging activity and bioavailability.Artif. Cells Nanomed. Biotechnol.201947160962010.1080/21691401.2019.1573739 30831030
    [Google Scholar]
  135. SaraswatB. VisenP.K.S. AgarwalD.P. Ursolic acid isolated from Eucalyptus tereticornis protects against ethanol toxicity in isolated rat hepatocytes.Phytother. Res.200014316316610.1002/(SICI)1099‑1573(200005)14:3<163::AID‑PTR588>3.0.CO;2‑D 10815008
    [Google Scholar]
/content/journals/coc/10.2174/0113852728320575240719052529
Loading
/content/journals/coc/10.2174/0113852728320575240719052529
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test